Identification of a vesicular ATP release inhibitor for the treatment of neuropathic and inflammatory pain
| Autor: | Yoshiro Kitahara, Masatoshi Nomura, Kazuhiro Shima, Hiroshi Omote, Tsuyoshi Inoue, Ken Iwatsuki, Yoshinori Moriyama, Miki Hiasa, Yasuo Endo, Nao Hasuzawa, Reiko Ichikawa, Takaaki Miyaji, Yuri Kato, Atsushi Kadowaki |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Multidisciplinary Allosteric modulator Microglia business.industry medicine.medical_treatment Purinergic receptor Chronic pain Inflammation Pharmacology Bisphosphonate medicine.disease 03 medical and health sciences 030104 developmental biology Nociception medicine.anatomical_structure PNAS Plus In vivo medicine medicine.symptom business |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America. 114(31) |
| ISSN: | 1091-6490 |
| Popis: | Despite the high incidence of neuropathic and inflammatory pain worldwide, effective drugs with few side effects are currently unavailable for the treatment of chronic pain. Recently, researchers have proposed that inhibitors of purinergic chemical transmission, which plays a key role in the pathological pain response, may allow for targeted treatment of pathological neuropathic and inflammatory pain. However, such therapeutic analgesic agents have yet to be developed. In the present study, we demonstrated that clodronate, a first-generation bisphosphonate with comparatively fewer side effects than traditional treatments, significantly attenuates neuropathic and inflammatory pain unrelated to bone abnormalities via inhibition of vesicular nucleotide transporter (VNUT), a key molecule for the initiation of purinergic chemical transmission. In vitro analyses indicated that clodronate inhibits VNUT at a half-maximal inhibitory concentration of 15.6 nM without affecting other vesicular neurotransmitter transporters, acting as an allosteric modulator through competition with Cl−. A low concentration of clodronate impaired vesicular ATP release from neurons, microglia, and immune cells. In vivo analyses revealed that clodronate is more effective than other therapeutic agents in attenuating neuropathic and inflammatory pain, as well as the accompanying inflammation, in wild-type but not VNUT−/− mice, without affecting basal nociception. These findings indicate that clodronate may represent a unique treatment strategy for chronic neuropathic and inflammatory pain via inhibition of vesicular ATP release. |
| Databáze: | OpenAIRE |
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